title: Pml represses tumour progression through inhibition of mTOR.
abstract: The promyelocytic leukaemia gene PML is a pleiotropic tumour suppressor. We have recently demonstrated that PML opposes mTOR-HIF1α-VEGF signalling in hypoxia. To determine the relevance of PML-mTOR antagonism in tumourigenesis, we have intercrossed Pml null mice with Tsc2 heterozygous mice, which develop kidney cysts and carcinomas exhibiting mTOR upregulation. We find that combined inactivation of Pml and Tsc2 results in aberrant TORC1 activity both in pre-tumoural kidneys as well as in kidney lesions. Such increase correlates with a marked acceleration in tumour progression, impacting on both the biology and histology of kidney carcinomas. Also, Pml inactivation decreases the rate of loss of heterozygosity (LOH) for the wt Tsc2 allele. Interestingly, however, aberrant TORC1 activity does not accelerate renal cystogenesis in Tsc2/Pml mutants. Our data demonstrate that activation of mTOR is critical for tumour progression, but not for tumour initiation in the kidney.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Division of Genetics, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. bernardi.rosa@hsr.it
authors.forename: Rosa
authors.initials: R
authors.lastname: Bernardi
authors.forename: Antonella
authors.initials: A
authors.lastname: Papa
authors.forename: Ainara
authors.initials: A
authors.lastname: Egia
authors.forename: Nadia
authors.initials: N
authors.lastname: Coltella
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000473:pathology; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D006651:Histocytochemistry; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011860:Radiography, Abdominal; D012097:Repressor Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C519509:Crtc1 protein, mouse; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases